This proposal consists of three interrelating but different projects dealing with important aspects of polyketide chemistry and biochemistry. These are: (1) SYNTHESIS. This project is divided into two parts. (1-1) Asymmetric Synthesis. Because of the special significance of asymmetric induction clearly recognized in complex natural products synthesis, we plan to explore methodologies for effecting (near-) perfect asymmetric induction in fundamental organic reactions, including (a) the aldol reaction (to construct some basic 1,3-diol systems), (b) the Diels-Alder reaction, (c) hydroboration, (d) ketone reduction, and (e) epoxidation. (1-1) Total synthesis of bryostatin 1 (C47H68O17), a marine product (isolated from Bugula neritina) that exhibits significant biological activities as demonstrated by a 52-95% extension of the average lifetime of leukemic mice. (2) CONFORMATIONAL ANALYSIS OF POLYHYDROXYLATED ACYCLIC SYSTEMS. We will continue our attempts to establish reliable computer programs for the conformational analysis of polyhydroxylated acyclic systems which are often embedded in natural products of biological significance (e.g. palytoxin) as well as in synthetic intermediates leading to these compounds. Thus, NMR spectroscopy will serve the purpose of determining the solution conformation of these acyclic systems. (3) MECHANISTIC STUDIES ON THE CARBON-CARBON BOND FORMING REACTION CATALYZED BY BETA-KETOACYL THIOLASE. With an abundant supply of the pure thiolase isolated from Zoogloea ramigera now in our hands, we will launch a long-range project aimed at the mechanistic elucidation of this bilogical Claisen condensation. Elaborate kinetic studies to be undertaken first will be followed by the amino acid sequencing of the enzyme through the gene-cloning technique. The three-dimensional view of the catalyst through crystallography and the mechanistic interpretation of the enzymatic reaation will complete the project. Efforts to answer the fundamental question of how the enzyme lowers Delta H as well as Delta S will bring about, at the end, a new concept or concepts in designing catalysts and reagents, an important goal of organic chemistry.